CN101061128B - Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate - Google Patents
Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate Download PDFInfo
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- CN101061128B CN101061128B CN2005800221766A CN200580022176A CN101061128B CN 101061128 B CN101061128 B CN 101061128B CN 2005800221766 A CN2005800221766 A CN 2005800221766A CN 200580022176 A CN200580022176 A CN 200580022176A CN 101061128 B CN101061128 B CN 101061128B
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- -1 di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate Chemical class 0.000 title claims description 21
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims description 13
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 150000003009 phosphonic acids Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 4
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- QEWYKACRFQMRMB-UHFFFAOYSA-N monofluoroacetic acid Natural products OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical group [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 229940083608 sodium hydroxide Drugs 0.000 claims 1
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 8
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 229940127073 nucleoside analogue Drugs 0.000 abstract 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 abstract 1
- 241000700721 Hepatitis B virus Species 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- SNRMSFWQDNTNHM-UHFFFAOYSA-N C(C)(C)OP(OC(C)C)(O)C Chemical compound C(C)(C)OP(OC(C)C)(O)C SNRMSFWQDNTNHM-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- ZANNOFHADGWOLI-UHFFFAOYSA-N ethyl 2-hydroxyacetate Chemical compound CCOC(=O)CO ZANNOFHADGWOLI-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Chemical group 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000002710 Ilex cornuta Nutrition 0.000 description 2
- 241001310146 Ilex cornuta Species 0.000 description 2
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 239000011630 iodine Chemical group 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-UHFFFAOYSA-N 0.000 description 1
- 238000006129 Kulinkovich cyclopropane synthesis reaction Methods 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- RCTAUTYWHCUQKC-UHFFFAOYSA-N [Li].C(CCC)[O] Chemical group [Li].C(CCC)[O] RCTAUTYWHCUQKC-UHFFFAOYSA-N 0.000 description 1
- LDDQLRUQCUTJBB-UHFFFAOYSA-N ammonium fluoride Chemical compound [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention relates to a new process for preparing diisopropyl { [l-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate (2), which is a key intermediate for synthesizing an antiviral (particularly, against hepatitis B virus) nucleoside analogue. The present invention also relates to new intermediates, and a process for preparing the antiviral nucleoside analogue from the compound (2) prepared according to the present invention.
Description
Technical field
The present invention relates to the novel method of the compound of a kind of preparation following formula (2),
It is the key intermediate of antiviral (especially anti-hepatitis B virus) nucleoside analog of synthetic following formula (1).
The invention still further relates to new intermediate, and from the method for formula prepared in accordance with the present invention (2) compound (following is compound (2)) preparation formula (1) compound (following for compound (1)).
Background technology
Compound (1) is a kind of resistance of hepatitis B therapeutical agent (korean patent application No.2002-0003051, WO 02/057288), and compound (2) can be used as the critical reactants of preparation compound (1) with the compound of following formula (3),
Wherein X represents fluorine, chlorine, bromine or iodine.
Well-known purine derivative such as compound (1) have anticancer and antiviral activity, and ten kinds (10) or more this analog derivatives comprise that AZT, 3TC, ACV etc. are for commercial applications.
Compound (2) prepares according to the method for reaction process as follows 1 as the important intermediate of preparation compound (1),
Reaction process 1
The method of top flow process 1 uses following formula (4) ethyl glycollate as starting raw material.
In the method for flow process 1, the ethyl glycollate of formula (4) and the tertiary butyl (phenylbenzene) silyl chloropexia production (5) compound, itself and ethylmagnesium bromide and tetraisopropoxide titanium are according to prior art (Syn.Lett, 07,1053-1054, the ring propanol compounds of the currently known methods synthesis type (6) 1999) obtains its solid form then from heptane.Formula (6) compound dissolution that obtains is reacted production (7) compound in dimethyl formamide and with trimethyl carbinol lithium and brooethyl phosphonic acids diisopropyl ester.Formula (7) compound and Neutral ammonium fluoride reflux in methyl alcohol and generate compound (2).
Yet, in the above methods, because used brooethyl phosphonic acids diisopropyl ester is retained in the reaction soln in the step of synthesis type (7) compound, can gives and introduce impurity in the compound (2), and always in the compound that finally obtains (2), contain 7～15% amount.In addition, formula (6) compound can cause the indefinite and operational difficulty of yield to the unstable of trimethyl carbinol lithium in the step of synthesis type (7) compound.
Therefore, those skilled in the art wish to improve the purity of compound (2) and the stability of improvement type (6) compound in the process of synthesis type (7) compound.
Summary of the invention
Present inventors have carried out extensive studies to improving the method for preparing compound (2), found that the problems referred to above of being mentioned in the former technology can replace the tertiary butyl (phenylbenzene) silyl chloride to overcome as reactant by using trityl chloride, thereby obtain highly purified compound (2).The inventor also finds to have finished the present invention thus by making the highly purified compound (2) that obtains in this way obtain compound (1) with high yield.
Therefore, an object of the present invention is to provide the novel method of a kind of preparation compound (2).
Another object of the present invention provides the new intermediate that obtains in the process of preparation compound (2).
A further object of the present invention provides the method for a kind of compound that uses the method according to this invention to obtain (2) preparation as formula (1) nucleoside analog of antiviral agent.
The invention provides a kind of method for preparing compound (2), may further comprise the steps: make the trityl fluoroacetic acid ethyl ester of formula (4) compound and trityl chloride prepared in reaction following formula (8),
Make formula (8) compound and ethyl halogenation reactive magnesium prepare the 1-trityl oxygen methyl-ring propyl alcohol of following formula (9),
The 1-trityl oxygen methyl-ring propyl alcohol of formula (9) and brooethyl phosphonic acids diisopropyl ester in solvent, in the presence of alkali, combine, (the 1-trityl oxygen methyl-ring third oxygen the methyl)-phosphonic acids diisopropyl ester of the following formula (10) of preparation solid form,
The trityl group of formula (10) compound is converted into hydroxyl.
When implementing method of the present invention, N-Methyl pyrrolidone (NMP) is more preferably as the ring propoxy-of formula (9) and the solvent in the phosphonate groups integrating step, thereby obtains output and all better formula (2) compound of purity.
Method of the present invention can be shown in following reaction process 2.
Reaction process 2:
Wherein X represents fluorine, chlorine, bromine or iodine.
The preferable amount of every kind of reactant and reaction conditions comprise that temperature of reaction and purification process will be elaborated below.
Used at first, in this manual abbreviation is defined as follows:
Tr: trityl
Et: ethyl
EDC:1, the 2-ethylene dichloride
THF: tetrahydrofuran (THF)
EA: ethyl acetate
I Pr: sec.-propyl
LTB: trimethyl carbinol lithium
The NMP:N-methyl-2-pyrrolidone
DBMP: brooethyl phosphonic acids diisopropyl ester
MTBE: methyl tertiary butyl ether
TFA: trifluoroacetic acid
MDC: methylene dichloride
AN: acetonitrile
Min: minute
In the reaction of the ethyl glycollate of the first step formula (4) and trityl chloride, 1.0 normal trityl chlorides (TrCl) and 1～1.3 normal pyridine are joined in 1.0～1.5 normal formula (4) compounds, mixture is being stirred under the condition that EDC exists under about 30～60 ℃.After stirring end, obtain formula (8) compound through the acid-alkali treatment mixture, it is handled through hexane and is converted into solid form then, perhaps just is used for next step reaction without being further purified.Introduce 2.1～3.1 normal ethyl magnesium halides in formula (8) compound, preferred ethylmagnesium chloride or ethylmagnesium bromide and 0.2～0.6 normal tetraisopropoxide titanium, under 5～15 ℃, carry out Kulinkovich reaction (J.Am.Chem.Soc., 1995,117,9919-9920).Then, to wherein adding the minor official aqueous acid of Chinese holly, stirred reaction mixture extracts and obtains formula (9) compound.With formula (9) compound dissolution in solvent, especially be preferably dissolved among the NMP, to wherein adding 1.3～1.7 normal DBMP and 1.5～2.0 normal LTB, stirred the mixture 6～19 hours under 45 ℃ the condition and obtain formula (10) compound being no more than through acid-alkali treatment.Gained formula (10) compound is handled through heptane at low temperatures and is converted into solid form.The H that in formula (10) compound, adds 1.5～2.5 normal TFA and 0.1～0.5 /g
2O at room temperature stirs the mixture.After stirring end, through acid-alkali treatment, filter the solid that produces, extraction obtains compound (2).Here preferably utilize sodium hydroxide to carry out this acid-alkali treatment, carry out this extraction with methylene dichloride.
Method of the present invention can prepare purity up to 98～100% compound (2).
And formula (9) and (10) compound itself of obtaining as the intermediate of method of the present invention are exactly new compound.Therefore, the present invention further provides these new midbody compounds.
The compound (2) of above method preparation is the key intermediate of synthetic above-mentioned formula (1) nucleoside analog.Particularly, the method for preparing compound (1) may further comprise the steps: go up at compound (2) and introduce leavings group and prepare the compound of following formula (11)
Wherein, L represents leavings group, and preferred mesyloxy, tolysulfonyl oxygen base or halogen make formula (11) compound and formula (3) compound coupling prepare the compound of following formula (12)
Wherein the definition of X is the same, the compound of hydrolyzing type (12) compound following formula (13)
Wherein the definition of X is the same, removes the X group in formula (13) compound and simultaneously tertiary butyl phosphinylidyne oxygen ylmethyl group is incorporated into the phosphonic acids part.
The detailed reaction conditions of aforesaid method be described in the applicant in first to file (korean patent application No.2002-0003051, WO 02/057288).Therefore, the invention provides a kind of method of coming preparation formula (1) compound by formula (2) compound that makes from the method shown in the reaction process 2.
The present invention will do more detailed explanation in the following embodiments.Yet these embodiment should be understood to just illustrate rather than by any way scope of the present invention is limited of the present invention.
In the following embodiments, the HPLC condition finished of assaying reaction is as follows:
[HPLC condition]
Pillar: Capcell pak C18 (model: MG 5; Size: 4.6 I.D * 250)
Wavelength (λ): 254
Flow velocity: 1.0 /min
Gradient condition: beginning: 20/80 (H
2O/AN, 0.1%TFA), 5min:20/80,7min:0/100,10min:0/100,12min:20/80
Embodiment
Embodiment 1: the preparation of trityl fluoroacetic acid ethyl ester (8)
(279g 1.0mol) is dissolved in (680,5 /g is with respect to ethyl glycollate) among the EDC, and (135g 1.3mol) joins in the mixture with ethyl glycollate with trityl chloride.(99g 1.25mol), and down stirs mixture 19 hours at 40 ℃ to wherein adding pyridine.Reaction is after HPLC confirms to finish, and the aqueous hydrochloric acid (270,2 /g is with respect to ethyl glycollate) that adds 0.5N makes reaction soln become two phase liquid, then extraction.After carrying out single extraction again, decompression steams EDC.In order to obtain the solid form of formula (8) compound, (680) joins in the spissated compound with hexane, and temperature is reduced to 0 ℃, stirs the mixture about 3 hours and filtration.
[HPLC]
Compound: TrCl compound (8)
Retention time (RT): 5.38 8.58
Area %:2.39 83.93
1H?NMR(400MHz，CDCl
3)δ1.23(t，3H，J＝8Hz)，3.78(s，2H)，4.14(q，2H，J＝8Hz)，7.26～7.22(m，3H)，7.33～7.29(m，6H)，7.50～7.47(m，6H)
13C?NMR(400MHz，CDCl
3)δ10.8，57.3，59.3，84.0，123.9，124.6，125.3，140.0，166.7
The preparation of embodiment 2:1-trityl oxygen methyl-ring propyl alcohol (9)
Tetrahydrofuran (THF) [1040,3 /g is with respect to formula (8) compound] being joined among the embodiment 1 in formula (8) compound of preparation, is 100% to be prerequisite with the yield of embodiment 1, and mixture is cooled to 0 ℃.To wherein add the tetraisopropoxide titanium (113.8g, 0.4mol), and 5～15 ℃ through 3～6 hours to wherein dripping ethylmagnesium bromide (concentration is 1M for 1500,3.0mol).Reaction adds 20% the minor official aqueous acid of Chinese holly [1790,5 /g is with respect to formula (8) compound], stir about one hour in being no more than 35 ℃ condition downhill reaction solution after HPLC confirms to finish.After stirring end, decompression steams tetrahydrofuran (THF) wherein, and residue extracted twice is for the first time with 1390 [4 /g is with respect to formula (8) compound] ethyl acetate, for the second time with 690 [2 /g is with respect to formula (8) compound] ethyl acetate.With the saturated NaHCO of the organic layer that obtains thus
3Solution washing [690,2 /g is with respect to formula (8) compound], concentrating under reduced pressure obtains title product formula (9) compound.
[HPLC]
Compound: TrOH compound (9)
Retention time (RT): 5.40 6.23
Area %:5.07 78.54
1H?NMR(400MHz，CDCl
3)δ0.45(dd，2H，J＝8Hz)，0.80(dd，2H，J＝8Hz)，2.59(s，1H)，3.18(s，2H)，7.23～7.32(m，9H)，7.45～7.47(m，6H)
13C?NMR(400MHz，CDCl
3)δ8.4，51.9，63.9，83.0，123.7，124.6，125.3，140.5
The embodiment 3:(1-trityl oxygen methyl-ring third oxygen methyl)-preparation of phosphonic acids diisopropyl ester (10)
Formula (9) compound (261.25g that obtains through concentrating under reduced pressure to embodiment 2,0.79mol) (supposition is 79% from the yield of formula (9) compound that embodiment 1 begins to obtain, because the peak area that HPLC measures is 78.54%) the middle NMP[1050 that adds, 4 /g is with respect to formula (9) compound] and DBMP (307g, 1.2mol).(107g 1.3mol), stirs the mixture being no more than under 45 ℃ the condition then to add LTB in reaction mixture.After about 6～19 hours, finish through HPLC confirmation reaction, to wherein adding 14%NH
4The Cl aqueous solution [1830,7 /g is with respect to formula (9) compound] comes termination reaction.To wherein adding MTBE[for twice for the first time: 1050,4 /g is with respect to formula (9) compound; 520 for the second time, 2 /g is with respect to formula (9) compound] be separated.Merge the organic layer that obtains thus and use the 21%NaCl aqueous solution [1650,6.3 /g is with respect to formula (9) compound] to wash.Remaining organic layer concentrating under reduced pressure, and to wherein adding heptane [1300,5 /g is with respect to formula (8) compound].Mixture is cooled to-10 ℃, about 3 hours after-filtration obtain formula (10) title compound (586g, purity 96.23%, yield 71.3%) of solid form.
[HPLC]
Compound: TrOH compound (9) compound (10)
Retention time (RT): 5.24 6.02 9.26
Area %:0.10 0.09 96.23
[NMR] do not observe other peak except the peak of formula (10) compound.
1H?NMR(400MHz，CDCl
3)δ0.54(dd，2H，J＝8Hz)，0.80(dd，2H，J＝8Hz)，1.33～1.29(m，12H)，3.22(s，2H)，3.92(d，2H，J＝8Hz)，4.67～4.76(m，2H)，7.21～7.31(m，9H)，7.43～7.46(m，6H)
13C?NMR(400MHz，CDCl
3)δ11.9，24.4，24.4，24.5，24.6，63.5，63.8，64.0，65.1，67.3，71.3，71.4，86.9，127.4，128.3，129.1，144.3
Embodiment 4:{[1-(methylol)-cyclopropyl] oxygen } preparation of methyl-phosphorous acid diisopropyl ester (2)
(59.15g 116.3mmol) is dissolved in the acetone [59.2,1 /g is with respect to formula (10) compound], to wherein adding H formula (10) compound that embodiment 3 is obtained
2O (5.9,327.8mmol) and TFA (26.52g 232.6mmol), stirs the mixture under the room temperature.Partly for being less than or equal at 7% o'clock,, remove acetone through HPLC confirmation formula (10) compound through underpressure distillation to the NaOH aqueous solution that wherein adds 3N [75,2.6 /g is with respect to formula (10) compound].Leach the solid that produces in the reaction, and filtrate is used twice of dichloromethane extraction [118.3 * 2,2 /g is with respect to formula (10) compound].The organic layer that concentrating under reduced pressure obtains thus obtains title compound (2) [the relative formula of yield (10) compound is 102.4% for 31.71g, purity 98%].
[HPLC]
Compound: TrOH compound (10)
Retention time (RT): 5.14 9.20
Area %:93.58 5.07
[NMR] only observes the peak of dichloromethane solvent except the peak of compound (2).
1H?NMR(400MHz，DMSO)δ0.55(dd，2H，J＝8Hz)，0.72(dd，2H，J＝8Hz)，1.22～1.24(m，12H)，3.32(s，2H)，3.53(d，2H，J＝4Hz)，3.81(d，2H，J＝8Hz)，4.53～4.72(m，2H)，4.73(t，1H)
13C?NMR(400MHz，DMSO)δ7.44，20.7，20.75，20.85，20.88，58.81，60.47，60.69，61.62，61.77，67.12，67.18
As explained above such, when trityl chloride used according to the invention, the midbody compound of formula (10) can obtain with solid form, and this has just solved problems of the prior art is that brooethyl phosphonic acids diisopropyl ester does not have to remove but be retained in the compound (2) to cause its purity drop.Especially, if select N-Methyl pyrrolidone to replace the solvent of dimethyl formamide as preparation formula (10) compound, formula (9) thus compound improves purity and the yield that influences compound (2) in an advantageous manner widely to the stability of tertiary butyl oxygen lithium.And, effective preparation that can come high yield as the compound (1) of antiviral agent by the highly purified compound (2) that uses acquisition according to the present invention.
Claims (8)
1. method for preparing the compound of following formula (2), this method may further comprise the steps:
Make the compound of following formula (4)
With the trityl fluoroacetic acid ethyl ester of trityl chloride prepared in reaction following formula (8),
Formula (8) compound and ethyl halogenation reactive magnesium prepare the 1-trityl oxygen methyl-ring propyl alcohol of following formula (9),
The 1-trityl oxygen methyl-ring propyl alcohol of formula (9) and brooethyl phosphonic acids diisopropyl ester in solvent, in the presence of alkali, combine, (the 1-trityl oxygen methyl-ring third oxygen the methyl)-phosphonic acids diisopropyl ester of the following formula (10) of preparation solid form,
The trityl group of formula (10) compound is converted into hydroxyl.
2. the process of claim 1 wherein that making solvent used in the step of formula (9) compound prepared in reaction formula (10) compound is N-Methyl pyrrolidone.
3. claim 1 or 2 method, wherein making alkali used in the step of formula (9) compound prepared in reaction formula (10) compound is trimethyl carbinol lithium.
4. claim 1 or 2 method, wherein the ethyl magnesium halide is ethylmagnesium chloride or ethylmagnesium bromide.
5. claim 1 or 2 method, wherein ethyl magnesium halide and formula (8) compound reacts in the presence of the tetraisopropoxide titanium.
6. claim 1 or 2 method, the trityl in its Chinese style (10) compound are converted into the product of gained behind the hydroxyl through sodium-hydroxide treatment, leach the solid of generation, and filtrate obtains formula (2) compound with dichloromethane extraction.
7. following formula (9) compound:
Wherein Tr represents trityl.
8. following formula (10) compound:
Wherein Tr represents trityl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020040051558 | 2004-07-02 | ||
| KR10-2004-0051558 | 2004-07-02 | ||
| KR1020040051558A KR101033290B1 (en) | 2004-07-02 | 2004-07-02 | New process for preparing diisopropyl 1-hydroxymethyl-cyclopropyloxymethylphosphonate |
| PCT/KR2005/002007 WO2006004330A1 (en) | 2004-07-02 | 2005-06-27 | Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate |
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| CN101061128A CN101061128A (en) | 2007-10-24 |
| CN101061128B true CN101061128B (en) | 2010-10-06 |
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| CN2005800221766A Active CN101061128B (en) | 2004-07-02 | 2005-06-27 | Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate |
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| US (2) | US7795463B2 (en) |
| EP (1) | EP1765838A4 (en) |
| JP (1) | JP4422183B2 (en) |
| KR (1) | KR101033290B1 (en) |
| CN (1) | CN101061128B (en) |
| AR (1) | AR049566A1 (en) |
| AU (1) | AU2005260375B8 (en) |
| BR (1) | BRPI0512886A (en) |
| CA (1) | CA2571592C (en) |
| MX (1) | MXPA06015262A (en) |
| NZ (1) | NZ552246A (en) |
| RU (1) | RU2326885C1 (en) |
| TW (1) | TWI326685B (en) |
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| CL2008000070A1 (en) * | 2007-01-17 | 2008-07-25 | Lg Life Sciences Ltd | MALEIC ACID MONOSAL (3 - [({1 - [(2-AMINO-9H-PURIN-9-IL) METHYL] CICLOPROPIL} OXI) METHYL] -8,8-DIMETHYL-3,7-DIOXO-2,4 , 6-TRIOXA-3 LAMBDA 5-PHOSPHANON-1-IL-PIVALATE; PHARMACEUTICAL COMPOSITION THAT INCLUDES THE SUCH MONOSAL; AND USE FOR THE TREATMENT OF VIRUS H |
| CN106432330B (en) * | 2015-08-11 | 2019-02-01 | 天津科伦药物研究有限公司 | The midbody compound and its preparation method and application of LB80380 drug |
| KR102694680B1 (en) | 2016-08-01 | 2024-08-14 | 삼성디스플레이 주식회사 | Electronic device, mounting method of the same, and method of manufacturing display apparatus having the same |
| CN108997429B (en) * | 2018-07-27 | 2020-10-30 | 广州粤美医药科技有限公司 | Method for preparing Beciclovir |
| CN115181013B (en) * | 2022-07-22 | 2023-08-08 | 北京先通国际医药科技股份有限公司 | Preparation method and application of key intermediate of modified fatty acid type PET reagent precursor |
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| WO2005079812A1 (en) * | 2004-02-17 | 2005-09-01 | Lg Life Sciences Ltd. | Nucleoside phosphonate derivatives useful in the treatment of hiv infections |
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| US5688778A (en) * | 1989-05-15 | 1997-11-18 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Nucleoside analogs |
| AU661347B2 (en) * | 1991-10-11 | 1995-07-20 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral acyclic phosphonomethoxyalkyl substituted, alkenyl and alkynyl purine and pyrimidine derivatives |
| US5817647A (en) * | 1993-04-01 | 1998-10-06 | Merrell Pharmaceuticals Inc. | Unsaturated acetylene phosphonate derivatives of purines |
| GB0117950D0 (en) * | 2001-02-16 | 2001-09-19 | Aventis Pharma Inc | Novel heterocyclic urea derivatives andd their use as dopamine D3 receptor ligands |
| US20060111324A1 (en) * | 2002-09-26 | 2006-05-25 | Lg Life Sciences | (+)-Ttrans-isomers of (1-phosphonomethoxy-2-alkylcyclopropyl)methyl nucleoside derivatives, process for the preparation of stereoisomers thereof, and use of antiviral agents thereof |
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| CN1487949A (en) * | 2001-01-19 | 2004-04-07 | ��ʽ����LG������ѧ | Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
| WO2005079812A1 (en) * | 2004-02-17 | 2005-09-01 | Lg Life Sciences Ltd. | Nucleoside phosphonate derivatives useful in the treatment of hiv infections |
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| Publication number | Publication date |
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| CN101061128A (en) | 2007-10-24 |
| EP1765838A1 (en) | 2007-03-28 |
| NZ552246A (en) | 2009-07-31 |
| AU2005260375B8 (en) | 2011-01-20 |
| AU2005260375B2 (en) | 2010-12-09 |
| ZA200610744B (en) | 2008-05-28 |
| US20090187019A1 (en) | 2009-07-23 |
| RU2007104036A (en) | 2008-08-10 |
| CA2571592A1 (en) | 2006-01-12 |
| BRPI0512886A (en) | 2008-04-15 |
| CA2571592C (en) | 2010-02-09 |
| RU2326885C1 (en) | 2008-06-20 |
| JP4422183B2 (en) | 2010-02-24 |
| US7795463B2 (en) | 2010-09-14 |
| KR20060002501A (en) | 2006-01-09 |
| JP2008505066A (en) | 2008-02-21 |
| AU2005260375A1 (en) | 2006-01-12 |
| TW200606170A (en) | 2006-02-16 |
| WO2006004330A1 (en) | 2006-01-12 |
| EP1765838A4 (en) | 2009-05-27 |
| KR101033290B1 (en) | 2011-05-09 |
| US20100305364A1 (en) | 2010-12-02 |
| AR049566A1 (en) | 2006-08-16 |
| TWI326685B (en) | 2010-07-01 |
| MXPA06015262A (en) | 2007-03-21 |
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